3-methyl-2-phenylmethoxybenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(benzyloxy)-3-methylbenzaldehyde (20 g, 88.39 mmol, 1.00 equiv), propanedioic acid (27.6 g, 265.23 mmol, 3.00 equiv), piperidine (1.5 g, 17.62 mmol, 0.20 equiv) and pyridine (200 mL). The resulting solution was heated to reflux for 2 h in an oil bath. The reaction was then quenched by the addition of 1.5 L of water/ice. The pH value of the solution was adjusted to 2-3 with hydrogen chloride. The solids were collected by filtration. The filter cake was washed with 2×500 mL of water and 2×500 mL of hexane. This resulted in 21 g (89%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid as a white solid. MS (ESI) m/z 269 ([M+H]+). Into a 500-mL 3-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting solution was heated to reflux for 2 h in an oil bath The reaction was then quenched by the addition of 1.5 L of water/ice The solids were collected by filtration The filter cake was washed with 2×500 mL of water and 2×500 mL of hexane This resulted in 21 g (89%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid as a white solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [2-(benzyloxy)-3-methylphenyl]methanol (30 g, 131.41 mmol, 1.00 equiv) and DMSO (300 mL). This was followed by the addition of 2-iodoxybenzoic acid (41 g, 146.42 mmol, 1.10 equiv) in several batches. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 1.5 L of ethyl acetate. The resulting mixture was washed with 3×800 mL of brine. The mixture was dried over anhydrous sodium sulfate. This resulted in 30 g (crude) of 2-(benzyloxy)-3-methylbenzaldehyde as orange oil. MS (ESI) m/z 227 ([M+H]). Into a 500-mL 3-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting mixture was washed with 3×800 mL of brine The mixture was dried over anhydrous sodium sulfate This resulted in 30 g (crude) of 2-(benzyloxy)-3-methylbenzaldehyde as orange oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a nitrogen stream, to a solution of 2-benzyloxy-3-methyl-benzaldehyde (1.87 g, 8.25 mmol) in THF (50 mL), a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 19.8 mL) was added dropwise under cooling with ice. The mixture was stirred at room temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (2.76 g, 100%). under cooling with ice under cooling with ice the mixture was extracted with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried (anhydrous magnesium sulfate) the solvent was distilled under reduced pressure The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a nitrogen stream, to a solution of 2-benzyloxy-3-methyl-benzaldehyde (1.87 g, 8.25 mmol) in THF (50 mL), a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 19.8 mL) was added dropwise under cooling with ice. The mixture was stirred at room temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (2.76 g, 100%). under cooling with ice under cooling with ice the mixture was extracted with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried (anhydrous magnesium sulfate) the solvent was distilled under reduced pressure The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-hydroxy-3-methylbenzaldehyde (3.0 g, 22.07 mmol) in N,N-dimethylformamide (50 mL), potassium carbonate (3.65 g, 26.4 mmol) was added and furthermore benzyl bromide (2.9 mL, 24.2 mmol) was added thereto. The mixture was stirred at room temperature for 26 hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (5.0 g, 100%). the mixture was extracted with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried (anhydrous magnesium sulfate) the solvent was distilled under reduced pressure The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)]

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Benzyloxy-3-methylbenzaldehyde prepared by the above 2-(1) 20.0 g (88.4 mmol) was dissolved in methylene chloride 100 ml and thereto was added m-chloroperbenzoic acid 16.8 g (97.2 mmol). The mixture was reacted at 20° C. under stirring for 10 hours. After disappearance of the raw material, the solution was neutralized with a saturated sodium bicarbonate solution and extracted with methylene chloride. To the extract (2-benzyloxy-3-formyloxytoluene) was added a 10% sodium hydroxide solution 38.9 g (97.2 mmol) in the ice bath and the mixture was stirred for 3 hours. The reaction mixture was neutralized with a 5% hydrochloric acid solution and extracted with methylene chloride. The solvent was removed in vacuo and the residue was purified in the same manner as in the above mentioned 3-(1) to give 2-benzyloxy-3-methylphenol 16.7 g (yield: 88%). The mixture was reacted at 20° C. extracted with methylene chloride To the extract (2-benzyloxy-3-formyloxytoluene) the mixture was stirred for 3 hours extracted with methylene chloride The solvent was removed in vacuo the residue was purified in the same manner as in the

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Benzyloxy-3-methylbenzaldehyde prepared by the above 2-(1) 20.0 g (88.4 mmol) was dissolved in methanol 100 ml and thereto was added sulfuric acid 20.0 g (203 mmol) and then added 30% hydrogen peroxide 30.1 g (265 mmol). The mixture was refluxed for 2 hours. After disappearance of the raw material, the solution was concentrated in vacuo, neutralized with a saturated sodium bicarbonate solution and extracted with methylene chloride. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate) to give 2-benzyloxy-3-methylphenol 13.3 g (yield: 70%). The mixture was refluxed for 2 hours After disappearance of the raw material, the solution was concentrated in vacuo extracted with methylene chloride The solvent was removed in vacuo the residue was purified by silica gel chromatography (n-hexane-ethyl acetate)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Hydroxy-3-methylbenzaldehyde 20.0 g (147 mmol) prepared by the above 1-(1) was dissolved in dimethylformamide (DMF) (100 ml) and to the solution was added potassium carbonate 31.0 g (221 mmol) and thereto was dropped benzyl bromide 25.0 g (147 mmol). The reaction mixture was stirred for 2 hours at 20° C. After disappearance of the raw material, the reaction mixture was filtrated and the solvent was removed in vacuo and the residue was purified in the same manner as in the above 2-(1) to give 2-benzyloxy-3-methylbenzaldehyde 24.2 g (yield: 73%). After disappearance of the raw material, the reaction mixture was filtrated the solvent was removed in vacuo the residue was purified in the same manner as in the above 2-(1)